WO2011113351A1 - Composés [(4-méthyl-2-propyl-n-méthoxy-substitués de phénylalkyl-1h-benzimidazol-6-formamide)-1-yl]-méthylbiphényle et procédés de préparation associés - Google Patents

Composés [(4-méthyl-2-propyl-n-méthoxy-substitués de phénylalkyl-1h-benzimidazol-6-formamide)-1-yl]-méthylbiphényle et procédés de préparation associés Download PDF

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Publication number
WO2011113351A1
WO2011113351A1 PCT/CN2011/071846 CN2011071846W WO2011113351A1 WO 2011113351 A1 WO2011113351 A1 WO 2011113351A1 CN 2011071846 W CN2011071846 W CN 2011071846W WO 2011113351 A1 WO2011113351 A1 WO 2011113351A1
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Prior art keywords
methyl
methoxy
compound
benzimidazole
added
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PCT/CN2011/071846
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English (en)
Chinese (zh)
Inventor
周智明
章军
李志怀
汪进良
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北京理工大学
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Publication of WO2011113351A1 publication Critical patent/WO2011113351A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to [(4-methyl-2-propylmethoxy substituted phenylalkyl-1H-benzimidazole-6-carboxamide)-1- which is used as an angiotensin ⁇ ATi receptor antagonist
  • the methyl]biphenyl compound, a preparation method and a pharmaceutical composition belong to the field of medical technology. Background technique
  • Hypertension is the most common cardiovascular disease, and its complications are one of the leading causes of human death and a major public health problem worldwide. China is in a period of rapid social and economic development. With the transformation of society and the aging of the population, people's living standards and behaviors have undergone tremendous changes, and the prevalence of hypertension has also shown a rapid upward trend. There are 160 million people with high blood pressure among adults in China, and more than 6 million new hypertensive patients are added each year. Therefore, it is particularly important to strengthen prevention and treatment of hypertension.
  • Non-peptide angiotensin ⁇ ATi receptor antagonist is a new class of antihypertensive drugs acting on the renin-angiotensin system (RAS), compared with angiotensin converting enzyme inhibitor (ACEI).
  • RAS renin-angiotensin system
  • ACEI angiotensin converting enzyme inhibitor
  • the antihypertensive effect is more significant, and the RAS is more selectively blocked, and the side effects are small.
  • ARB drugs such as losartan, valsartan, telmisartan, irbesartan and candesartan.
  • telmisartan has the highest activity, but its structure is complex and the synthesis is relatively difficult. Therefore, it is important to simplify its structure and synthesize new highly active compounds. Summary of the invention
  • the object of the present invention is to solve the problems of complex structure and relatively difficult synthetic difficulty of the ARB antihypertensive drug telmisartan, and to provide a [[4-methyl-] for synthesizing a new highly active compound.
  • the [(4-methyl-2-propylmethoxy substituted phenylalkyl-1H-benzimidazole-6-carboxamide)-1-yl]methylbiphenyl compound of the present invention has the following formula: Wherein n is 1 or 2; is 2-methoxy, 3-methoxy, 4-methoxy, 3,4-dimethoxy or 2,5-dimethoxyphenyl; R 2 is Carboxyl or tetrazolyl.
  • P is a methoxycarbonyl group or a trityltetrazolyl group.
  • N-methoxy substituted phenylalkylamine is any one represented by the following formula:
  • the passage of the intermediate A is as follows:
  • n 1 or 2; is 2-methoxy, 3-methoxy, 4-methoxy, 3,4-dimethoxy or 2, 5- Dimethoxy;
  • n 1 or 2; is 2-methoxy, 3-methoxy, 4-methoxy, 3,4-dimethoxy or 2, 5- Dimethoxy; P is methoxycarbonyl or trityltetrazolyl;
  • the molar ratio of the compound C to the aqueous sodium hydroxide solution is 1: 5;
  • P represents a trityltetrazolyl group
  • the compound C is added to the solvent tetrahydrofuran and methanol, and then 10% hydrochloric acid is added thereto, and the reaction is stirred at room temperature for 12 hours ; the reaction mixture is adjusted to pH 12 with 2 mol/L sodium hydroxide, and then the reaction mixture is adjusted to pH 12 with 2 mol/L sodium hydroxide.
  • the present invention provides a pharmaceutical composition for treating cardiovascular and cerebrovascular diseases, which comprises a therapeutically effective amount of the above [(4-methyl-2-propylmethoxy substituted phenylalkyl-1H-benzimidazole- 6-carboxamide)-1-yl]methylbiphenyl compounds and pharmaceutically conventional excipients.
  • the pharmaceutical composition according to the present invention can be obtained by a conventional method of pharmacy.
  • the present invention provides a method for treating cardiovascular and cerebrovascular diseases, which comprises administering to a patient suffering from cardiovascular and cerebrovascular diseases a therapeutically effective amount of the above [(4-methyl-2-propylmethoxy substituted phenylalkyl-1H-benzene) And imidazole-6-carboxamide-1-yl]methylbiphenyl compounds.
  • the beneficial effects of the present invention are as follows:
  • the compound of the present invention has a good angiotensin A ATi receptor inhibitory activity, and can be used for preparing a medicament for treating cardiovascular and cerebrovascular diseases, and an aqueous solution thereof is directly reacted with sodium hydroxide or potassium hydroxide.
  • the sodium salt or potassium salt of the product has simple structure and synthesis process, and the raw material is easy to obtain, and is suitable for China's national conditions. Detailed ways
  • reaction mixture was naturally warmed to room temperature and reacted at room temperature for 5 h.
  • the reaction solution was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and water, dried and evaporated to dryness.
  • Amino) -1H-benzimidazole-6-carboxamide 2.63 g.
  • the total yield in two steps was 77.9 %.
  • IR KBr vmax/cm- 1 3308, 1727, 1631, 1590, 1544, 1458, 1288, 1244, 1129;
  • the methoxy-substituted phenylalkylamine is 10 mmol of 4-methoxybenzylamine, and the other feeding and carrying methods are the same as in the step (1) of Example 1, the product is a white solid 4-methyl-2-propyl -N-(4-Methoxybenzylamino)-1H-benzimidazole-6-carboxamide, yield 71.4%, m.p. 133 - 135.
  • IR KBr vmax/cm- 1 3357, 1652, 1593, 1533 , 1511, 1454, 1293, 1245, 1041, 880,
  • the methoxy-substituted phenylalkylamine is 10 mmol 3,4-dimethoxybenzylamine, and the other conditions and methods are the same as in the step (1) of Example 1, and the product is a white solid 4-methyl- 2-propyl-N-(3,4-dimethoxybenzylamino)-1H-benzimidazole-6-carboxamide, yield 75.0%, m.p.
  • the methoxy-substituted phenylalkylamine is 10 mmol 2,5-dimethoxyphenethylamine, and the other preparation and implementation methods are the same as in the step (1) of Example 1, and the product is a white solid 4-methyl.
  • IR KBr ax/cm- 1 3361 , 1654, 1597, 1536, 1501, 1465, 1355, 1291, 1244, 1039, 809, 764;
  • step (2) of 1 Replacing 4'-bromomethylbiphenyl-2-carboxylic acid methyl ester with 4'-bromomethylbiphenyl-2-(2'-N-triphenylmethyl)tetrazole, other conditions are the same as in the examples In step (2) of 1, the product is a white solid 4-methyl-2-propyl-N-(2-methoxybenzylamino)-1-[2'-(1-tritylmethyltetrazole -5-yl)biphenyl-4-yl]methylbenzimidazole-6-carboxamide, yield 86.3%.
  • IR KBr ix/cm- 1 3263 , 1635, 1591, 1536, 1492, 1458, 1392, 1275, 1240, 1119, 1026, 877, 754;
  • the methoxy-substituted phenylalkylamine is 10 mmol 3-methoxyphenethylamine, and the other feeding and carrying out methods are the same as in the step (1) of Example 1, the product is a white solid 4-methyl-2- Propyl-indole 3-methoxyphenethylamino)-1H-benzimidazole-6-carboxamide, yield 75.7%.
  • IR KBr vmax/cm- 1 3427, 1637, 1593, 1541, 1457, 1352, 1262, 1215, 1149, 1093, 875, 757;
  • the methoxy-substituted phenylalkylamine is 10 mmol 4-methoxyphenethylamine, and the other preparation and implementation methods are the same as in the step (1) of Example 1, and the product is a white solid 4-methyl-2- Propyl-indole 4-methoxyphenethylamino)-1H-benzimidazole-6-carboxamide, yield 76.6%, mp 149 ⁇ 151 °C.
  • the methoxy-substituted phenylalkylamine is 10 mmol of 3,4-dimethoxyphenethylamine, and the other preparation and implementation methods are the same as in the step (1) of Example 1, and the product is a white solid 4-methyl.
  • reagents were added sequentially to a 96-well culture plate (COSTAR, USA): AT i Receptor 15 ⁇ /well (diluted to 2.0 ⁇ ⁇ /well with assay buffer, pre-warmed at 37 °C buffer), ⁇ 0.1 % DMSO, tested Add 10 ⁇ of different concentrations of test drug to the tube, add 10 ⁇ of deionized water to the tube, add 1 mg / mL Angiotensin II standard ⁇ (55 ⁇ / well) to the tube, and incubate at 37 °C for 30 min. , [ ⁇ -Sar 1 is added to each hole.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de [(4-méthyl-2-propyl-N-méthoxy-substitués de phénylalkyl-1H-benzimidazol-6-formamide)-1-yl]-méthylbiphényle de formule I, ainsi que des procédés de préparation et des utilisations associés. Ces procédés de préparation adoptent les voies synthétiques suivantes. Les composés selon l'invention peuvent servir dans la fabrication de médicaments destinés au traitement des maladies cardio-vasculaires et cérébro-vasculaires. Ces composés présentent une bonne activité d'inhibition des récepteurs AT1 de l'angiotensine II. Les procédés de préparation selon l'invention présentent l'avantage qu'ils mettent en oeuvre un processus de synthèse simple et que les matières premières sont faciles à obtenir. En outre, ces procédés peuvent être utilisés avantageusement dans la production industrielle.
PCT/CN2011/071846 2010-03-18 2011-03-16 Composés [(4-méthyl-2-propyl-n-méthoxy-substitués de phénylalkyl-1h-benzimidazol-6-formamide)-1-yl]-méthylbiphényle et procédés de préparation associés WO2011113351A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201010126447A CN101798287A (zh) 2010-03-18 2010-03-18 [（4-甲基-2-丙基-n-甲氧基取代苯烷基-1h-苯并咪唑-6-甲酰胺）-1-基]甲基联苯类化合物及制备方法
CN201010126447.5 2010-03-18

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Publication number Priority date Publication date Assignee Title
CN101798287A (zh) * 2010-03-18 2010-08-11 北京理工大学 [（4-甲基-2-丙基-n-甲氧基取代苯烷基-1h-苯并咪唑-6-甲酰胺）-1-基]甲基联苯类化合物及制备方法
CN102491971B (zh) * 2011-12-19 2017-03-01 北京理工大学 手性[(4-甲基-2-丙基-1h-苯并咪唑-6-酰胺)-1-基]甲基联苯类化合物及其制备方法和用途
CN110105338A (zh) * 2019-05-31 2019-08-09 东华大学 6’-取代胺甲酰基苯并咪唑-4-取代甲基吲哚衍生物
CN112745302A (zh) * 2019-10-31 2021-05-04 上海中医药大学附属龙华医院 苯并咪唑类化合物及其医药用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0566020A1 (fr) * 1992-04-11 1993-10-20 Dr. Karl Thomae GmbH Benzimidazoles, médicaments les contenant et procédé pour leur préparation
WO2008153857A1 (fr) * 2007-06-05 2008-12-18 Theravance, Inc. Agents antihypertenseurs de benzimidazole à double effet
WO2009004064A1 (fr) * 2007-07-03 2009-01-08 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de telmisartan
WO2009116089A2 (fr) * 2008-03-14 2009-09-24 Ipca Laboratories Limited Nouveaux intermédiaires et procédé de synthèse de 4'-[(1,4'-diméthyl-2'-propyl-[2,6'- bi-1hbenzimidazol]-l-yl)méthyl]-1,1-biphényl]-2-acide carboxylique
CN101798287A (zh) * 2010-03-18 2010-08-11 北京理工大学 [（4-甲基-2-丙基-n-甲氧基取代苯烷基-1h-苯并咪唑-6-甲酰胺）-1-基]甲基联苯类化合物及制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101921265B (zh) * 2009-11-25 2012-07-04 北京理工大学 联苯酰胺四唑类化合物、合成方法及用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0566020A1 (fr) * 1992-04-11 1993-10-20 Dr. Karl Thomae GmbH Benzimidazoles, médicaments les contenant et procédé pour leur préparation
WO2008153857A1 (fr) * 2007-06-05 2008-12-18 Theravance, Inc. Agents antihypertenseurs de benzimidazole à double effet
WO2009004064A1 (fr) * 2007-07-03 2009-01-08 Krka, Tovarna Zdravil, D.D., Novo Mesto Procédé de préparation de telmisartan
WO2009116089A2 (fr) * 2008-03-14 2009-09-24 Ipca Laboratories Limited Nouveaux intermédiaires et procédé de synthèse de 4'-[(1,4'-diméthyl-2'-propyl-[2,6'- bi-1hbenzimidazol]-l-yl)méthyl]-1,1-biphényl]-2-acide carboxylique
CN101798287A (zh) * 2010-03-18 2010-08-11 北京理工大学 [（4-甲基-2-丙基-n-甲氧基取代苯烷基-1h-苯并咪唑-6-甲酰胺）-1-基]甲基联苯类化合物及制备方法

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